N-Methyl levo benzomorphan analgesics having non-addictive and morphine antagonistic properties

ABSTRACT

Analgesic activity in man and animals is effected by administering an acid addition salt of the levo isomer of a compound of the structure ##STR1## wherein R is a lower alkyl group and R 1  is a member of the group consisting of hydrogen and lower alkyl groups. Certain of the levo isomers are novel compounds.

This application is a continuation of application Ser. No. 45,553 filed June 11, 1970, which is a continuation-in-part of application Ser. No. 801,209 filed Feb. 20, 1969, now abandoned. which is a cintinuation-in-part of application Ser. No. 643,382 filed June 5, 1967, all are now abandoned.

This invention relates to novel analgesics and a method of effecting analgesic activity in man and animals by the administration of an acid addition salt of the levo isomer of a benzomorphan compound of the structure. ##STR2## wherein R is a lower alkyl group and R₁ is a member of the group consisting of hydrogen and lower alkyl groups.

It is an object of this invention to provide novel analgesics and new analgesic methods employing active compounds of low toxicity, which are not habit-forming but exhibit morphine antagonism. Other objects and advantages will be apparent to those skilled in the art from the description herein.

The racemates of the above identified benzomorphan compounds are known to have analgesic properties.

The levo (-) isomers are twice as potent as the racemates, have no physical dependence capacity in monkeys but exhibit morphine antagonism whereas the racemates exhibit no such antagonism. The levo isomers are nalorphine-like.

The racemate, α-(+5,9diethyl-2'-hydroxy-2-methyl-6,7benzomorphan may be resolved into its optical isomers by means of d-mandelic acid (+)-3-bromo-8-camphorsulfonic acid, 1-mandelic acid or d-10-camphorsulfonic acid. Detailed procedures for resolution by these methods have been published by us in the Journal of Medicinal Chemistry, 9, 851-852 (1966) which is incorporated by reference in this application.

The racemates of the 5-methyl, the 5-ethyl and 5-propyl, 9-methyl compounds may be resolved by procedures set forth in detail herein.

The compounds are administered in the form of a water-soluble acid addition salts. Suitable salts include the hydrochloride, methyl sulfate, acetate, citrate, hydrobromide, nitrate, phosphate and tartrate, by way of example.

The compositions according to the present invention also comprise a pharmaceutical carrier which may be either a solid material or a liquid. Preparations for oral ingestion can be liquids or solids or any combination of these forms, such as syrups, elixirs, powders or tablets. Preparations for administration of the active agent in unit dose form can take the form of compressed powders or tablets or of a powder enclosed in a suitable capsule or absorbable material such as gelatin. The compressed powders or tablets may also comprise suitable excipients and/or diluents such as starch, lactose, stearic acid, magnesium stearate, dextrin or polyvinyl pyrrolidone.

Preparations for parenteral administration may be sterile solutions or suspensions in liquids such as water or physiological saline and may contain soluble or insoluble diluents and/or liquid excipients.

The unit dosage or therapeutically effective quantity of the analgetic agents of this invention may vary over wide limits; about 5to 25mg./kg. of body weight for injectable compositions and about 20to 100mg./kg. of body weight for oral preparation.

The pain relieving capacity of the levo isomers of the invention are about equivalent to that of morphine but they possess no physical dependency liability in monkeys.

The pharmacological properties of the optical isomers are set forth in the following table:

    __________________________________________________________________________     Compound.sup.a                                                                          ED.sub.50.sup.b                                                                     PDC.sup.c                                                                             Antagonistic Activity.sup.c                               __________________________________________________________________________     (-) 5,9-dimethyl                                                                        0.9  No.sup.d                                                                              1/50-1/30 Nalorphine                                      (+) 5,9-dimethyl                                                                        Inactive                                                                            No     No                                                        (-) 5,9-diethyl                                                                         1.2  No.sup.e                                                                              1/10 Nalorphine                                           (+) 5,9-diethyl                                                                         7.9  Intermediate                                                                          No                                                        (-) 5-methyl                                                                            1.8  No.sup.f                                                                              1/50 Nalorphine                                           (+) 5-methyl                                                                            22.9 Very low                                                                              No                                                        (-) 5-ethyl                                                                             0.6  No.sup.g                                                                              1/40-1/20 Nalorphine                                      (+) 5-ethyl                                                                             21.8 Low    No                                                        (-) 5-propyl,                                                                           0.8  No.sup.h                                                                              1/5 Nalorphine                                              9-methyl                                                                     (+) 5-propyl,                                                                           12.3 High   No                                                          9-methyl                                                                     Morphine 1.2  High   No                                                        Codeine  7.5  Intermediate                                                                          No                                                        __________________________________________________________________________      .sup.a Administered as hydrochloride salts in water excepting morphine (a      sulfate).                                                                      .sup.b Expressed in mg/kg (mice, subcutaneous administration); cf, N.B.        Eddy and D. Leimbach, J. Pharmacol, Exptl. Therap., 107, 385 (1953) and        A.E. Jacobson and E.L. May, J. Med. Chem., 8, 563 (1965).                      .sup.c cf. Refs. 2, 3, and 4.                                                  .sup.d From 0.5-8 mg/kg.                                                       .sup.e From 0.5-32 mg/kg.                                                      .sup.f From 1.0-20 mg/kg.                                                      .sup.g From 2-16 mg/kg.                                                        .sup.h From 0.5-2 mg/kg.                                                 

The following examples illustrate suitable therapeutic compositions:

EXAMPLE I

The following was prepared:

    ______________________________________                                         χ-(-)-5,9-diethyl-2'-hydroxy-                                              2-methyl-6,7-benzomorphan hydrochloride                                                                   15 g.                                               water                      1000 g.                                             ______________________________________                                    

The water was distilled, pyrogen-free water. The solution was sealed in ampoules and sterilized after sealing for use for hypodermic injection.

EXAMPLE II

Tablets were prepared from the following (per tablet):

    ______________________________________                                         χ-(-)-5-propyl, 9-methyl-2'-hydroxy-                                       2-methyl-6,7-benzomorphan hydrochloride                                                                 250 mg.                                               lactose                  200 mg.                                               starch                   40 mg.                                                stearic acid             5 mg.                                                 sodium carboxymethyl cellulose                                                                          0.2 mg.                                               ______________________________________                                    

The CMC sodium salt was dispersed in water, the dispersion mixed with the remaining ingredients except stearic acid, the mixture passed through a 12 mesh standard sieve, dried, mixed with the stearic acid and compressed into tablets.

EXAMPLE III

Example I was repeated employing (-)-5-methyl-2'-hydroxy-2methyl-6,7-benzomorphan hydrochloride.

EXAMPLE IV (-)5-methyl-2'

Example I was repeated employing (-)-5-ethyl-2'hydroxy-2-methyl-6,7-benzomorphan hydrochloride.

EXAMPLE V

Example II was repeated employing α-(-)-5,9-diethyl-2'-hydroxy-2-methyl-6,7-benzomorphan acetate.

The following examples set forth the detailed resolutions of the racemates:

EXAMPLE VI α- (±)-5-methyl-2'-hydroxy-2-methyl-6,7-benzomorphan

The racemate (2.2g), 1.8 g (1.15 equiv) of 1-mandelic acid (Aldrich Chemical Company, Inc.), 10 ml of acetone and 1 ml of methanol were heated to solution and left at 25° for 3 hr and at -5° for 18 hr; yield 1.7 g, mp 175°-185°. This white solid, recrystallized from methanol gave 1.2 g of the (-)-1-mandelate, mp 190°-192°, which in methanol-aqueous ammonia yielded 0.65 g (60%) of 1(-)free base; mp 211°-212°, [α]²⁰ D -72.5°, after a recrystallization from acetone or methanol. Anal. (C₁₄ H₁₉ NO) C, H; the Hydrochloride (from absolute ethanol-HCl then recrystallization from absolute ethanol), mp 262°-265°, [α]²⁰ D -49.6°. Anal. (C₁₄ H₂₀ CINO) C, H.

The combined filtrates (from the 1.7 g of 1-mandelate and from recrystallization of this 1.7 g) were concentrated to 2-3 ml and treated with excess aqueous ammonia to give 1.5 g of base mixture. This material, 1.2 g of d-mandelic acid (Aldrich), 6 ml of acetone and 2 ml of methanol were warmed to solution, cooled and kept at -5° for 1 hr to give 1.7 g of white solid, mp 184°-188°. One recrystallization from 5-6 ml of methanol gave 1.3 g of the (+)-d-mandelate, mp 191°-192.5° in turn converted to 0.7 g (63%) of the (+)-free base, mp 209°-210.5°, [α]²⁰ D +74.5°, after a recrystallization from acetone. Anal. (C₁₄ H₁₉ NO) C, H; the hydrochloride (from methanol-acetone) had mp 262°-265°, [α]²⁰ D +49.1°.

EXAMPLE VII α-(± )-5ethyl-2'-hydroxy-2-methyl-6,7-benzomorphan

The racemate (5.0 g), 3.3 g of d-mandelic acid, 13 ml of absolute ethanol and 5 ml of acetone were heated to solution, filtered and left at 25° overnight to give 1.7 g (41%) of white solid which was recrystallized from methanol (4 ml) - acetone (15 ml). Cooling to 0° gave 0.9 g of the (-)-d-mandelate, mp 170.5°-172°, [α]²⁰ D +25.1). Anal. (C₂₃ H₂₉ NO₄) C, H. It gave 0.5 g of the (-) free base from aqueous ammonia; mp 208°-210° [α]²⁰ D -49.7°. Anal. (C₁₅ H₂₁ NO) C, H. The hygroscopic hydrochloride (from ethereal HCl) was recrystallized from methanol-acetone and carefully dried for 3 hr at 100° in vacuo just prior to analysis; mp 186.5°-188.5°, sealed capillary. Anal. (C₁₅ H₂₂ CINO) C, H.

The combined filtrates (from isolation and recrystallization of the (-)-d-mandelate were concentrated to 7-10 ml, made basic with dilute ammonia diluted with H₂ O, and cooled to give 4.3 g of a mixture of racemate and the d-isomer. This mixture, 2.8 g of 1-mandelic acid, 8 ml of methanol and 35 ml of acetone were warmed to solution, filtered and the filter washed with acetone. The combined filtrate and washings were distilled to half volume, diluted with acetone and again distilled to half volume. Addition of acetone to 75 ml and refrigeration gave a white solid which was recrystallized from absolute ethanol (11 ml)-acetone (25 ml) giving 1.3 g (31%) of the (+)-1-mandelate, mp 170.5°-171.5°, [α]²⁰ D-21.3°. Anal. (C₂₃ H₂₉ NO₄) C, H. The (+) base melted at 209.5°-211.5° and had [α]²⁴ D+51°. Anal. (C₁₅ H₂₁ NO) C, H. The hydrochloride had mp 188°-189° and was hygroscopic like the enantiomer. Anal. (C₁₅ H₂₂ CINO) C, H.

EXAMPLE VIII α-(±)-5-propyl-9-methyl-2'-hydroxy-2-methyl-6,7-benzomorphan

Absolute ethanol (20 ml(, 2.0 g of racemate and 2.0 g of d-10-camphorsulfonic acid (Eastman) were heated to solution and left at room temperature for 6 hr to give 1.3 g of square plates, mp 245°-247° after filtration and washing with cold ethanol. This salt yielded 0.65 g (65%) of the (+) free base (from aqueous methanol-ammonia), mp 235°-237°, [α]²⁰ D+69.8°, after a recrystallization from methanol. Anal. (C₁₇ H₂₅ NO) C, H, N. The hydrochloride (from isopropanol-diethyl ether) had mp 166°-169°, [α]²⁰ D+50.8°. Anal. (C₁₇ H₂₆ CINO) C, H, Cl.

The filtrate and washings from the 1.3 g of square plates above were made basic with ammonia and diluted with an equal volume of water. Cooling gave 1.2 g of the 1-free base and racemate which, with 0.8 g of d-mandelic acid was heated to solution in 5ml of acetone. After 6 hr at 25° 1.1 g of the (-)-d-mandelate, mp 209°-211°, was filtered and converted to 0.65 (65%) of the (-) free base, mp 236°-238°, [α]²⁰ D-70.0, with methanol-dilute aqueous ammonia. Anal. (C₁₇ H₂₅ NO) C, H, N. The hydrochloride melted at 166°-169°; [α]²⁰ D-49.3. Anal. (C₁₇ H₂₆ CINO) C, H.

Analytical values were within ±0.3% of the theoretical values. Rotations in 95% ethanol (free bases and mandelate salts) and water (hydrochloride salts) were taken on a Perkin Elmer 141 Polarimeter, concentrations 1.0-1.4 g/100 ml of solution. Melting points (capillary) are corrected and expressed in ° C.

REFERENCES

(1) N. B. Eddy and E. L. May, "Synthetic Analgesics," Part II (B), 6,7-Benzomorphans," Pergamon Press, London, 1966, P 138 ff.

(2) G. A. Deneau, J. E. Villarreal, and M. H. Seevers, Addendum 2, Minutes of the 28th and 30th Meeting of the Committee on Problems of Drug Dependence, 1966, 1968, and J. E. Villarreal personal communication.

(3) J. E. Villarreal and M. H. Seevers, personal communication. 

We claim:
 1. A method of effecting analgesic and morphine antagonistic activity without producing physical dependence in animals which comprises administering to an animal an effective dosage of an acid addition salt of the levo isomer of a compound of the structure ##STR3## wherein R is a lower alkyl group and R₁ is hydrogen or a lower alkyl group, with the proviso that R and R₁ may not both be methyl.
 2. The method of claim 1 wherein said compound is α-(-)-5,9-diethyl-2' -hydroxy-2--methyl-6,7-benzomorphan
 3. The method of claim 1 wherein said compound is (-)-5-methyl-2'-hydroxy-2-methyl-6,7-benzomorphan.
 4. The method of claim 1 wherein said compound is (-)-5-ethyl-2'-hydroxy-2-methyl-6,7-benzomorphan.
 5. The method of claim 1 wherein said compound is α-(-)-5-propyl-9-methyl-2'-hydroxy-2;l -methyl-6,7-benzomorphan.
 6. The method of claim 1 wherein said salt is the hydrochloride.
 7. The method of claim 6 wherein said compound is α-(-)-5,9-diethyl-2'-hydroxy-2-methyl-6,7-benzomorphan.
 8. The method of claim 6 wherein said compound is (-)-5-methyl-2'-hydroxy-2-methyl-6,7-benzomorphan.
 9. The method of claim 6 wherein said compound is (-)-5-ethyl-2'- hydroxy-2-methyl-6,7-benzomorphan.
 10. The method of claim 6 wherein said compound is α-(-)-5-propyl-9-methyl-2'-hydroxy-2-methyl-6,7-benzomorphan.
 11. A pharmaceutical composition for internal administration having an analgesic, non-addictive, morphine-antagonistic effect which comprises a pharmaceutical carrier and an effective amount of an acid addition salt of α-(-)-5,9-diethyl-2-methyl hydroxy2-methyl-6,7-benzomorphan.
 12. The composition of claim 11 wherein said salt is the hydrochloride.
 13. The composition of claim 11 wherein said salt is the acetate.
 14. A pharmaceutical composition for internal administration having an analgesic, non-addictive, morphineantagonistic effect which compises a pharmaceutical carrier and an effective amount of an acid addition salt of the levo isomer of a compound of the structure ##STR4## wherein R is a lower alkyl group and R₁ is hydrogen or a lower alkyl group, with the proviso that R and R₁ may not both be methyl.
 15. The composition of claim 14, wherein said salt is the hydrochloride.
 16. The composition of claim 14, wherein said salt is the acetate.
 17. The composition of claim 14, wherein said compound is (-)-5-methyl-2'- -hydroxy-2-methyl-6,7-benzomorphan. methyl-6,7-benzomorphan.
 18. The composition of claim 14, wherein said compound is (-)-5-ethyl-2'-hydroxy-2- methyl-6,7-benzomorphan.
 19. The composition of claim 14, wherein said compound is α-(-)-5-propyl-9-methyl-2'-hydroxy-2-methyl-6,7-benzomorphan.
 20. An acid addition salt of the levo isomer of a compound of the structure. ##STR5## wherein R is a lower alkyl group and R₁ is hydrogen or a lower alkyl group, with the proviso that R and R₁ may not both be methyl.
 21. The salt of claim 20, wherein said salt is the hydrochloride.
 22. The salt of claim 20, wherein said salt is the acetate.
 23. The salt of claim 20, wherein said compound is α-(-)-5,9-diethyl-2'-hydroxy-2-methyl-6,7-benzomorphan.
 24. The salt of claim 20, wherein said compound is (-)-5-methyl-2'-hydroxy-2-methyl-6,7-benzomorphan.
 25. The salt of claim 20, wherein said compound is (-)-5-ethyl-2'-hydroxy-2-methyl-6,7-benzomorphan.
 26. The salt of claim 20, wherein said compound is α-(-)-5-propyl-9-methyl-2'-hydroxy-2-methyl-6,7-benzomorphan. 